Our group is studying cancer genetics, using the zebrafish genetic system to clarify developmental pathways subverted in human leukemias and solid tumors. The zebrafish model is an established system for studies of vertebrate embryogenesis, organ development and disease. A powerful attribute of the zebrafish model is the capacity to perform large-scale forward genetic screens on transparent, readily accessible embryos. These properties make the zebrafish an ideal system for identifying novel genes involved in cancer, as their discovery is based on unbiased phenotypic assays. This advantage is critical for dissecting pathways of gene action and identifying genes that are either activated (oncogenes) or inactivated (tumor suppressors) during malignant transformation.

We are currently conducting a genome-wide mutagenesis screen to identify genes required for normal myeloid cell development in the hematopoietic system. We have shown that zebrafish myelopoiesis is very similar to that in humans and other mammals, indicating that this screen should reveal conserved signal transduction pathways involved in normal vertebrate myeloid cell development. We postulate that a subset of the mutations identified by this approach will correspond to genes whose human counterparts contribute to the pathogenesis of two important human diseases - myelodysplastic syndrome and acute myeloid leukemia.

A second screen is underway to isolate genes that are disrupted in neuroblastoma, the most common extra-cranial solid tumor of children. These embryonic tumors arise from neuroectodermal cells derived from the neural crest, which normally contribute to the formation of the peripheral sympathetic nervous system (PSNS). Despite major modifications of therapy over the past two decades, the long-term cure rate in children with advanced disease is still far from satisfactory, posing daunting problems to therapists and experimental oncologists alike. Unfortunately, most of the genes that normally regulate development of the PSNS and neuroblastoma formation have not been identified. Using the zebrafish model, we have identified new genes required for normal PSNS development, and we are currently studying their roles in both PSNS development and the molecular pathogenesis of neuroblastoma.

A third area involves both transgenic and mutagenesis approaches in zebrafish to dissect pathways that lead to T-cell leukemia. We have shown that human T-cell leukemias can be divided into five major subtypes based on the expression of oncogenes that initiate malignant transformation in thymocytes. We recently showed that transgenic zebrafish overexpressing Myc develop T-ALL, which is histologically and pathologically similar to human T-ALL. We are now conducting one of the first Òcancer-relatedÓ modifier screens in a vertebrate system to identify both enhancers and suppressors of T-cell leukemia in the zebrafish.

Chemical and genetic modifier screens using tumor-prone zebrafish lines may ultimately reveal mutant genes or drugs that can suppress or modify disease progression. For example, we hope to identify mutated genes that promote specific aspects of the malignant phenotype, such as genomic instability, metastasis or invasiveness. We also hope to discover mutations or drugs that delay or totally suppress the onset tumors in transgenic zebrafish lines, thus providing candidate targets for the development of new therapies.